Method of solubilizing poorly soluble/insoluble active material through formation of oligomer composite

ABSTRACT

Provided is a method of solubilizing a poorly soluble/insoluble active material through formation of an oligomer composite, in which a structure having a hydrophobic cavity structure is formed by using oligomers derived from two types of hydrophilic natural polymers and a poorly soluble/insoluble component is encapsulated in the cavity structure, and thus, self-aggregation of the poorly soluble/insoluble material is prevented and simultaneously, thermodynamic stability increases to effectively solubilize the poorly soluble/insoluble material. According to the constitution of the present invention, the method may include a first operation of preparing an oligomer composite having a cavity structure formed therein by mixing and dissolving oligomers derived from two types of hydrophilic natural polymers in water, and a second operation of adding a poorly soluble/insoluble material to the oligomer composite to encapsulate the poorly soluble/insoluble material in the hydrophobic cavity structure of the oligomer composite.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application is a national stage filing of InternationalApplication No. PCT/KR2010/007066 which claims priority under 35 U.S.C.119 and 35 U.S.C. 365 to Korean Patent Application No. 10-2009-0121886filed on Dec. 9, 2009, which is hereby incorporated by reference in itsentirety.

BACKGROUND

The present disclosure relates to a method of solubilizing a poorlysoluble/insoluble active material through formation of an oligomercomposite, in which a structure having a hydrophobic cavity structure isformed by using oligomers derived from two types of hydrophilic naturalpolymers and a poorly soluble/insoluble component is encapsulated in thecavity structure, and thus, self-aggregation of the poorlysoluble/insoluble material is prevented and simultaneously,thermodynamic stability increases to effectively solubilize the poorlysoluble/insoluble material.

Recently, development of natural ingredients having excellentbiocompatibility and biostability as well as excellent biologicalactivity with respect to the human body has become more important indiscovering biologically active substances in cosmetics, food, andmedicine industries. However, some natural ingredients are unstableunder an acidic condition or others are unstable under a basiccondition. That is, characteristics of the active ingredients areoverall different and methods of sufficiently stabilizing activeingredients in a formulation are still in a development stage.

Therefore, natural ingredients currently having high efficacy and effectare expected to have a large potential value, but about 40% of theforegoing natural ingredients are not even in a development stage due toits low solubility. A process of increasing solubility of such amaterial poorly soluble in water or an aqueous solution by a certainmanipulation is denoted as “solubilization”. A typical technique able toimprove solubility and increase absorption of drugs may include a methodof using an organic solvent, such as ethanol, or surfactant as anadditive, a method of preparing as a salt form when an ionization groupis contained, and a method of increasing solubility by adjusting a pH,etc.

Recently, various attempts have also been made to improve typicallimitations of poorly soluble/insoluble materials by introducingliposome, microemulsion, cyclodextrin, and nanopowder techniques tosolubilize the poorly soluble/insoluble materials.

SUMMARY OF THE INVENTION

Embodiments provide a method of solubilizing a poorly soluble/insolubleactive material through formation of an oligomer composite, in which astructure having a hydrophobic cavity structure is formed by usingoligomers derived from two types of hydrophilic natural polymers and apoorly soluble/insoluble component is encapsulated in the cavitystructure, and thus, self-aggregation of the poorly soluble/insolublematerial is prevented and thermodynamic stability increases toeffectively solubilize the poorly soluble/insoluble material.

The technical objects of the present disclosure are not limited to theaforesaid, but other technical objects not described herein will beclearly understood by those skilled in the art from descriptions below.

In one embodiment, a method of solubilizing a poorly soluble/insolubleactive material through formation of an oligomer composite includes: afirst operation of preparing an oligomer composite having a cavitystructure formed therein by mixing and dissolving oligomers derived fromtwo types of hydrophilic natural polymers in water; and a secondoperation of adding a poorly soluble/insoluble material to the oligomercomposite to encapsulate the poorly soluble/insoluble material in thehydrophobic cavity structure of the oligomer composite.

In another embodiment, the method may further include, after the secondoperation: a third operation of removing a residual poorlysoluble/insoluble material unencapsulated in the oligomer composite byfiltration or centrifugation of a reaction solution; and a fourthoperation of removing water and an organic solvent (when used) from thereaction solution having the residual material removed therefrom to dry.

The details of one or more embodiments are set forth in the accompanyingdrawings and the description below. Other features will be apparent fromthe description and drawings, and from the claims.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates a structure, in which a poorly soluble/insolublematerial is encapsulated in a cavity structure of an oligomer compositeof the present invention.

DETAILED DESCRIPTION OF THE EMBODIMENTS

Reference will now be made in detail to the embodiments of the presentdisclosure, examples of which are illustrated in the accompanyingdrawings.

A basic concept of the present invention is that when poorlysoluble/insoluble materials are encapsulated in an oligomer compositehaving a hydrophobic cavity structure, precipitation of poorlysoluble/insoluble components in an aqueous solution is prevented bypreventing aggregation and re-aggregation of the poorlysoluble/insoluble components, dissolution stability is improved suchthat a chemical reaction able to change a structure of the poorlysoluble/insoluble components is not accompanied, and these componentsare encapsulated in an oligomer structure having a cavity structurephysically formed therein to maintain an inherent natural biologicalactivity as it is.

A method of preparing an oligomer composite according to the presentinvention includes: a first operation of preparing an oligomer compositehaving a physical cavity structure formed therein by mixing anddissolving oligomers derived from two types of hydrophilic naturalpolymers in water; and a second operation of adding a poorlysoluble/insoluble material to the oligomer composite to encapsulate thepoorly soluble/insoluble material in the hydrophobic cavity structure ofthe oligomer composite.

Two natural polymer oligomers are selected from the group consisting ofxanthan gum, acacia gum, guar gum, arabic gum, agar, alginic acid,chitosan, pectin, carboxyalkylcellulose, maltodextrin, dextrin, andhyaluronic acid, and then mixed.

Each weight ratio of two types of the selected natural polymer oligomerswith respect to distilled water is in a range of 1:1 to 1:10 and inparticular, may be in a range of 1:2 to 1:4. At this time, when theweight ratio of one natural polymer oligomer among the two types ofnatural polymer oligomers is too high, an encapsulation effect of apoorly soluble/insoluble active component may decrease because thehydrophobic cavity structure of the oligomer structure may not beproperly formed.

Also, a weight ratio between the two types of natural polymer oligomersand water is in a range of 1:1 to 1:100. When the weight ratio of thenatural polymer oligomers with respect to the water is too high,preparation of an oligomer composite solution may be difficult becauseviscosity of the solution may be excessively increased by the naturalpolymer oligomers. On the other hand, when the weight ratio of thenatural polymer oligomers with respect to the water is too low, theencapsulation effect of the poorly soluble/insoluble active componentmay decrease because the hydrophobic cavity structure may not beproperly formed due to a relatively low physical bonding force betweenmolecules of the oligomer composite in the aqueous solution. An averagemolecular weight of the natural polymer oligomer used may be in a rangeof 1,000 to 100,000.

Also, a preparation temperature during the preparation of the oligomercomposite may be within a range of 20° C. to 80° C., and in particular,the oligomer composite may be prepared within a temperature range of 40°C. to 50° C. At this time, a pH of the solution may be maintained in arange of 5 to 8. When the pH and temperature during the preparation ofthe oligomer composite are not controlled, the hydrophobic cavitystructure may not be properly formed, because the physical bonding forcebetween the molecules of the oligomer composite may decrease.

Meanwhile, in the second operation of adding a poorly soluble/insolublematerial to the oligomer composite to encapsulate the poorlysoluble/insoluble material in the hydrophobic cavity structure of theoligomer composite, the poorly soluble/insoluble material may be simplyadded or may be added by being dissolved in an organic solvent or thelike. The poorly soluble/insoluble material is slowly added to theoligomer composite solution formed in the first operation in an amountrange of 0.1 wt % to 99 wt % based on a total solid content. At thistime, the poorly soluble/insoluble material may be added in an amountrange of 1 wt % to 20 wt %. When the poorly soluble/insoluble materialis added in an amount more than 99 wt %, an effect of improvingsolubility of the poorly soluble/insoluble component may decrease,because it deviates from the capacity limit of the hydrophobic cavitystructure in the oligomer composite which may encapsulate the poorlysoluble/insoluble component.

When the poorly soluble/insoluble material is added in the secondoperation, an appropriate temperature is within a range of 20° C. to 80°C., and the poorly soluble/insoluble material may be mixed and stirredwithin a temperature range of 40° C. to 50° C. At this time, anappropriate pH is in a range of 5 to 8 and the pH may be maintained in arange of 6.5 to 7.5. When the temperature and pH are not controlled, thepoorly soluble/insoluble active component may not be properlyencapsulated in the oligomer composite, because the hydrophobic cavitystructure may collapse due to a decrease in the physical bonding forcebetween the natural polymer oligomers constituting the oligomercomposite.

Also, the organic solvent may be selected from the group consisting ofmethanol, ethanol, acetone, tetrahydrofuran (THF), and acetonitrile(AN).

The poorly soluble/insoluble materials may be selected from the groupconsisting of polyphenols, such as amentoflavone, ellagic acid,apigenin, berginin, diosmetin, univestin, resveratrol, isoflavones, andcatechin, oily fatty acids, such as salicylic acid, alpha lipoic acid,caffeine, tocopherol, docosahexaenoic acid (DHA), eicosapentaenoic acid(EPA), and conjugated linolenic acid (CLA), and natural extractscontaining a ginkgo biloba leaf extract, a red ginseng extract, andpolyphenols.

Meanwhile, after the second operation, the method may further include athird operation of removing a residual poorly soluble/insoluble materialunencapsulated in the oligomer composite by filtration or centrifugationof a reaction solution and a fourth operation of removing water and anorganic solvent (when used) from the reaction solution having theresidual material removed therefrom to dry.

The poorly soluble/insoluble materials are introduced to the oligomercomposite having the cavity structure to increase the solubility of thepoorly soluble/insoluble components and thus, dissolution stability maybe improved.

In the present invention, interaction between the two types of naturalpolymer oligomers is used to form the oligomer composite havinghydrophobic cavities and thus, structural density and physical bondingstrength may increase. Therefore, the solubility is improved byencapsulating a material having poorly soluble/insoluble characteristicsby physical bonding. [see FIG.1]

Hereinafter, the present invention will be described in detail,according to specific examples. However, the following examples aremerely presented to exemplify the present invention, and the scope ofthe present invention is not limited thereto.

CONTROL GROUP EXAMPLES 1 TO 12

One type of natural polymer oligomers was selected and added to 156 g ofdistilled water according to a ratio of the following Table 1. Areaction temperature was maintained in a range of 40° C. to 50° C., a pHwas maintained in a range of 5 to 8 by using a pH adjuster, and anoligomer aqueous solution was formed by being stirred until the oligomerwas completely dissolved.

The temperature and pH of the formed oligomer aqueous solution weremaintained in ranges of 40° C. to 50° C. and 6.5 to 7.5, respectively.An ellagic acid was used as a representative poorly soluble/insolublematerial and a predetermined amount of the ellagic acid was slowly addedto the oligomer aqueous solution. The ellagic acid was mixed and stirredwithin a temperature range of 40° C. to 50° C. At this time, the pH wasmaintained in a range of 6.5 to 7.5 to allow the ellagic acid to becompletely mixed in the oligomer aqueous solution. The prepared aqueoussolution was centrifuged and filtered to measure an amount ofprecipitates, and a filtrate was powdered by using a freeze dryer toprepare a control group.

TABLE 1 Use amount of Use amount Natural polymer from natural polymer ofellagic Control Group which oligomer is derived oligomer acid Examplederived (g) (g) Control Group Maltodextrin 40 4 Example 1 Control GroupDextrin 40 4 Example 2 Control Group Guar gum 40 4 Example 3 ControlGroup Arabic gum 40 4 Example 4 Control Group Acacia gum 40 4 Example 5Control Group Alginic acid 40 4 Example 6 Control Group Chitosan 40 4Example 7 Control Group Carboxymeth- 40 4 Example 8 ylcellulose ControlGroup Pectin 40 4 Example 9 Control Group Agar 40 4 Example 10 ControlGroup Xanthan gum 40 4 Example 11 Control Group Hyaluronic acid 40 4Example 12

[Experimental Method for Evaluating Solubility and Dissolution Stabilityof Control Group]

The ellagic acid was added to the solutions having the natural polymeroligomers dissolved therein and mixed during the preparation of thepowders of control group in Control Group Examples 1 to 12, and then theprecipitates were dried during centrifugation to measure weights ofinsoluble precipitates.

The prepared powders of the control group were weighed and put intodistilled water to make a volume of 100 ml, and aqueous solutions werethen prepared by stirring for 30 minutes. The prepared aqueous solutionswere put into centrifuge tubes, in which the weights thereof had beenpreviously measured, and centrifuged. Filtrates were removed and thetubes were dried in a vacuum drier at 60° C. for five days, and amountsof precipitates were then measured by measuring weight changes andsolubilities of the oligomer composites containing a poorlysoluble/insoluble material with respect to water were calculated. Thepresence of precipitates were visually observed while the centrifugedsupernatants were stored at 4° C. for zero week, one week, two weeks,three weeks, and four weeks.

The result of improvements in the solubility of poorly soluble/insolublematerial and the presence of precipitates with respect to control groupexamples are presented in Table 2.

TABLE 2 Input amount of powders Precipitate of amount controlPrecipitate Poorly during group amount Control soluble/ preparationduring during Group insoluble of control redissolution redissolutionSolubility Storage Presence of Example material group (g)¹⁾ (g) (g)(mg/ml) period precipitate²⁾ Control Ellagic 1.90 2.0 0.0 20.0 4 weeksOccurred in Group acid one week Example 1 Control Ellagic 1.90 2.0 0.020.0 4 weeks Occurred in Group acid one week Example 2 Control Ellagic1.95 2.0 0.0 20.0 4 weeks Occurred in Group acid one week Example 3Control Ellagic 1.94 2.0 0.0 20.0 4 weeks Occurred in Group acid oneweek Example 4 Control Ellagic 1.95 2.0 0.0 20.0 4 weeks Occurred inGroup acid one week Example 5 Control Ellagic 1.93 2.0 0.0 20.0 4 weeksOccurred in Group acid one week Example 6 Control Ellagic 1.95 2.0 0.020.0 4 weeks Occurred in Group acid one week Example 7 Control Ellagic1.96 2.0 0.0 20.0 4 weeks Occurred in Group acid one week Example 8Control Ellagic 1.95 2.0 0.0 20.0 4 weeks Occurred in Group acid oneweek Example 9 Control Ellagic 1.92 2.0 0.0 20.0 4 weeks Occurred inGroup acid one week Example 10 Control Ellagic 1.90 2.0 0.0 20.0 4 weeksOccurred in Group acid one week Example 11 Control Ellagic 1.91 2.0 0.020.0 4 weeks Occurred in Group acid one week Example 12 ¹⁾precipitateamount of ellagic acid undissolved during the preparation of singleoligomer composite containing an ellagic acid ²⁾storage period of 4weeks at 4° C., observation of the presence of precipitate

As shown in the result of Table 2, with respect to the control groupexamples in which single natural polymer oligomer was used, it may beunderstood that most of ellagic acid were precipitated instead of beingunencapsulated in the single natural polymer oligomer during theoligomer powders containing the ellagic acid were dissolved in water andcentrifuged. In order to investigate whether or not the solubilitieswere improved, the powders of the control group were redissolved andcentrifuged, and then weights of precipitates were measured. As aresult, the precipitates were not confirmed, but a residual ellagic acidwas precipitated in one week when the centrifuged supernatant was storedat 4° C. and thus, it may be understood that the control group did notaffect the improvement of the solubility of poorly soluble/insolublecomponent and the dissolution stability.

EXAMPLES 1 TO 120 Application of Oligomer Derived from Natural Polymer

Two types of natural polymer oligomers were mixed and added to 156 g ofdistilled water according to a ratio of the following Tables 3 to 5. Areaction temperature was maintained in a range of 40° C. to 50° C., a pHwas maintained in a range of 5 to 8 by using a pH adjuster, and anoligomer composite solution was formed by stirring until the oligomerswere completely dissolved.

Temperature and pH of the formed oligomer composite solution weremaintained in ranges of 40° C. to 50° C. and 6.5 to 7.5, respectively.An ellagic acid was used as a representative poorly soluble/insolublematerial and a predetermined amount of the ellagic acid was slowly addedto the oligomer composite solution. The ellagic acid was mixed andstirred within a temperature range of 40° C. to 50° C. At this time, thepH was maintained in a range of 6.5 to 7.5 to allow the ellagic acid tobe encapsulated in the hydrophobic cavity structure of the oligomercomposite. The reaction solution was centrifuged and filtered to measureweight of the unencapsulated and removed ellagic acid, and a supernatantor filtrate was powdered by using a freeze dryer to prepare an ellagicacid encapsulated oligomer composite.

TABLE 3 Use amount of Natural polymer from Use ellagic which oligomer isamount acid Example derived (g) (g) Example 1 Xanthan gum 10 4Maltodextrin 30 Example 2 Xanthan gum 10 4 Dextrin 30 Example 3 Xanthangum 10 4 Guar gum 30 Example 4 Xanthan gum 10 4 Arabic gum 30 Example 5Xanthan gum 10 4 Acacia gum 30 Example 6 Xanthan gum 10 4 Alginic acid30 Example 7 Xanthan gum 10 4 Chitosan 30 Example 8 Xanthan gum 10 4Carboxymethylcellulose 30 Example 9 Xanthan gum 10 4 Pectin 30 ExampleXanthan gum 10 4 10 Agar 30 Example Maltodextrin 10 4 11 Xanthan gum 30Example Maltodextrin 10 4 12 Dextrin 30 Example Maltodextrin 10 4 13Guar gum 30 Example Maltodextrin 10 4 14 Arabic gum 30 ExampleMaltodextrin 10 4 15 Acacia gum 30 Example Maltodextrin 10 4 16 Alginicacid 30 Example Maltodextrin 10 4 17 Chitosan 30 Example Maltodextrin 104 18 Carboxymethylcellulose 30 Example Maltodextrin 10 4 19 Pectin 30Example Maltodextrin 10 4 20 Agar 30 Example Dextrin 10 4 21Maltodextrin 30 Example Dextrin 10 4 22 Xanthan gum 30 Example Dextrin10 4 23 Guar gum 30 Example Dextrin 10 4 24 Arabic gum 30 ExampleDextrin 10 4 25 Acacia gum 30 Example Dextrin 10 4 26 Alginic acid 30Example Dextrin 10 4 27 Chitosan 30 Example Dextrin 10 4 28Carboxymethylcellulose 30 Example Dextrin 10 4 29 Pectin 30 ExampleDextrin 10 4 30 Agar 30 Example Guar gum 10 4 31 Maltodextrin 30 ExampleGuar gum 10 4 32 Dextrin 30 Example Guar gum 10 4 33 Xanthan gum 30Example Guar gum 10 4 34 Arabic gum 30 Example Guar gum 10 4 35 Acaciagum 30 Example Guar gum 10 4 36 Alginic acid 30 Example Guar gum 10 4 37Chitosan 30 Example Guar gum 10 4 38 Carboxymethylcellulose 30 ExampleGuar gum 10 4 39 Pectin 30 Example Guar gum 10 4 40 Agar 30 ExampleArabic gum 10 4 41 Maltodextrin 30 Example Arabic gum 10 4 42 Dextrin 30Example Arabic gum 10 4 43 Guar gum 30 Example Arabic gum 10 4 44Xanthan gum 30 Example Arabic gum 10 4 45 Acacia gum 30 Example Arabicgum 10 4 46 Alginic acid 30 Example Arabic gum 10 4 47 Chitosan 30Example Arabic gum 10 4 48 Carboxymethylcellulose 30

TABLE 4 Use amount of Natural polymer from Use ellagic which oligomer isamount acid Example derived (g) (g) Example Arabic gum 10 4 49 Pectin 30Example Acacia gum 10 4 50 Maltodextrin 30 Example Acacia gum 10 4 51Dextrin 30 Example Acacia gum 10 4 52 Guar gum 30 Example Acacia gum 104 53 Arabic gum 30 Example Acacia gum 10 4 54 Xanthan gum 30 ExampleAcacia gum 10 4 55 Alginic acid 30 Example Acacia gum 10 4 56 Chitosan30 Example Acacia gum 10 4 57 Carboxymethylcellulose 30 Example Acaciagum 10 4 58 Pectin 30 Example Acacia gum 10 4 59 Agar 30 Example Alginicacid 10 4 60 Maltodextrin 30 Example Alginic acid 10 4 61 Dextrin 30Example Alginic acid 10 4 62 Guar gum 30 Example Alginic acid 10 4 63Arabic gum 30 Example Alginic acid 10 4 64 Acacia gum 30 Example Alginicacid 10 4 65 Xanthan gum 30 Example Alginic acid 10 4 66 Chitosan 30Example Alginic acid 10 4 67 Carboxymethylcellulose 30 Example Alginicacid 10 4 68 Pectin 30 Example Alginic acid 10 4 69 Agar 30 ExampleChitosan 10 4 70 Maltodextrin 30 Example Chitosan 10 4 71 Dextrin 30Example Chitosan 10 4 72 Guar gum 30 Example Chitosan 10 4 73 Arabic gum30 Example Chitosan 10 4 74 Acacia gum 30 Example Chitosan 10 4 75Alginic acid 30 Example Chitosan 10 4 76 Xanthan gum 30 Example Chitosan10 4 77 Carboxymethylcellulose 30 Example Chitosan 10 4 78 Pectin 30Example Chitosan 10 4 79 Agar 30 Example Carboxymethylcellulose 10 4 80Maltodextrin 30 Example Carboxymethylcellulose 10 4 81 Dextrin 30Example Carboxymethylcellulose 10 4 82 Guar gum 30 ExampleCarboxymethylcellulose 10 4 83 Arabic gum 30 ExampleCarboxymethylcellulose 10 4 84 Acacia gum 30 ExampleCarboxymethylcellulose 10 4 85 Alginic acid 30 ExampleCarboxymethylcellulose 10 4 86 Chitosan 30 ExampleCarboxymethylcellulose 10 4 87 Xanthan gum 30 ExampleCarboxymethylcellulose 10 4 88 Pectin 30 Example Carboxymethylcellulose10 4 89 Agar 30 Example Pectin 10 4 90 Maltodextrin 30 Example Pectin 104 91 Dextrin 30 Example Pectin 10 4 92 Guar gum 30 Example Pectin 10 493 Arabic gum 30 Example Pectin 10 4 94 Acacia gum 30 Example Pectin 104 95 Alginic acid 30 Example Pectin 10 4 96 Chitosan 30

TABLE 5 Use amount of Natural polymer from Use ellagic which oligomer isamount acid Example derived (g) (g) Example Pectin 10 4 97Carboxymethylcellulose 30 Example Pectin 10 4 98 Xanthan gum 30 ExamplePectin 10 4 99 Agar 30 Example Agar 10 4 100 Maltodextrin 30 ExampleAgar 10 4 101 Dextrin 30 Example Agar 10 4 102 Guar gum 30 Example Agar10 4 103 Arabic gum 30 Example Agar 10 4 104 Acacia gum 30 Example Agar10 4 105 Alginic acid 30 Example Agar 10 4 106 Chitosan 30 Example Agar10 4 107 Carboxymethylcellulose 30 Example Agar 10 4 108 Pectin 30Example Agar 10 4 109 Xanthan gum 30 Example Hyaluronic acid 10 4 110Maltodextrin 30 Example Hyaluronic acid 10 4 111 Dextrin 30 ExampleHyaluronic acid 10 4 112 Guar gum 30 Example Hyaluronic acid 10 4 113Arabic gum 30 Example Hyaluronic acid 10 4 114 Acacia gum 30 ExampleHyaluronic acid 10 4 115 Alginic acid 30 Example Hyaluronic acid 10 4116 Chitosan 30 Example Hyaluronic acid 10 4 117 Carboxymethylcellulose30 Example Hyaluronic acid 10 4 118 Pectin 30 Example Hyaluronic acid 104 119 Agar 30 Example Hyaluronic acid 10 4 120 Xanthan gum 30

EXAMPLES 121 TO 138 Preparation of Oligomer Composite Containing PoorlySoluble/Insoluble Material

Dextrin and maltodextrin among natural polymer oligomers were added todistilled water according to a constant ratio as in the following Table6. A reaction temperature was maintained in a range of 40° C. to 50° C.,a pH was maintained in a range of 5 to 8 by using a pH adjuster, and anoligomer composite solution was formed by being stirred until thedextrin and maltodextrin were completely dissolved. The temperature andpH of the formed oligomer composite solution were maintained in rangesof 40° C. to 50° C. and 6.5 to 7.5, respectively. A predetermined amountof a poorly soluble/insoluble material was simply added to the oligomercomposite solution or dissolved in an organic solvent to obtain aconcentration of 1% to 50% and then the mixture was slowly added to theoligomer composite solution so as to allow the poorly soluble/insolublematerial to be encapsulated in a hydrophobic cavity structure of theoligomer composite solution. The reaction solution was centrifuged andfiltered to measure the weight of the unencapsulated and removed poorlysoluble/insoluble material, an organic solvent such as ethanol wasdistilled by using a distiller for experimental groups including theorganic solvent, and a supernatant or filtrate was powdered by using afreeze dryer to prepare an oligomer composite containing the poorlysoluble/insoluble material.

TABLE 6 Added amount of Name of poorly poorly Use amount Use amount Useamount of soluble/insoluble soluble/insoluble of distilled Category ofdextrin (g) maltodextrin (g) material material (g) water (g) Example 12110 30 Amentoflavone 4 156 Example 122 10 30 Diosmetin 4 156 Example 12310 30 Berginin 10 150 Example 124 10 30 Univestin 8 152 Example 125 1030 Apigenin 4 156 Example 126 10 30 Resveratrol 4 156 Example 127 10 30Isoflavones 8 152 Example 128 10 30 Salicylic acid 10 150 Example 129 1030 Alpha lipoic acid 8 152 Example 130 10 30 Caffeine 10 150 Example 13110 30 Tocopherol 8 152 Example 132 10 30 Docosahexaenoic 8 152 acidExample 133 10 30 Eicosapentaenoic 8 152 acid Example 134 10 30Conjugated 8 152 linolenic acid Example 135 10 30 Ginkgo biloba 4 156leaf extract Example 136 10 30 Red ginseng 4 156 extract Example 137 1030 Soybean extract 8 152 Example 138 10 30 Epigallocatechin 10 150gallate

[Experimental Method for Evaluating Solubility and Dissolution Stabilityof Examples]

The poorly soluble/insoluble material was added to the solutions havingtwo types of the natural polymer oligomers dissolved therein and mixedduring the preparation of the oligomer composites encapsulating thepoorly soluble/insoluble materials in Examples 1 to 138, and thenprecipitates were dried during centrifugation or filtration to measureweights of insoluble precipitates.

Oligomer composite powders encapsulating the poorly soluble/insolublematerial prepared in Examples 1 to 138 were weighed and put intodistilled water to make a volume of 100 ml, and aqueous solutions werethen prepared by stirring for 30 minutes. The prepared aqueous solutionswere put into centrifuge tubes, in which the weights thereof had beenpreviously measured, and centrifuged. Filtrates were removed and thetubes were dried in a vacuum drier at 60° C. for five days, and amountsof precipitates were then measured by measuring weight changes andsolubilities of the oligomer composites containing a poorlysoluble/insoluble material with respect to water were calculated. Thepresence of precipitates were visually observed while centrifugedsupernatants were stored at 4° C. for zero week, one week, two weeks,three weeks, and four weeks.

The result of improvements in the solubility of the poorlysoluble/insoluble material and the presence of precipitates with respectto Examples are presented in Tables 7 to 9.

TABLE 7 Input amount of oligomer composite Precipitate containing aamount poorly during soluble/insoluble Precipitate Poorly preparationmaterial amount soluble/ of oligomer during during Presence insolublecomposite redissolution redissolution Solubility Storage of Examplematerial (g)¹⁾ (g) (g) (mg/ml) period precipitate²⁾ Example 1 Ellagic0.03 2.0 0.0 20.0 4 weeks No acid Example 2 Ellagic 0.04 2.0 0.0 20.0 4weeks No acid Example 3 Ellagic 0.04 2.0 0.0 20.0 4 weeks No acidExample 4 Ellagic 0.04 2.0 0.0 20.0 4 weeks No acid Example 5 Ellagic0.04 2.0 0.0 20.0 4 weeks No acid Example 6 Ellagic 0.03 2.0 0.0 20.0 4weeks No acid Example 7 Ellagic 0.04 2.0 0.0 20.0 4 weeks No acidExample 8 Ellagic 0.04 2.0 0.0 20.0 4 weeks No acid Example 9 Ellagic0.04 2.0 0.0 20.0 4 weeks No acid Example Ellagic 0.04 2.0 0.0 20.0 4weeks No 10 acid Example Ellagic 0.04 2.0 0.0 20.0 4 weeks No 11 acidExample Ellagic 0.04 2.0 0.0 20.0 4 weeks No 12 acid Example Ellagic0.03 2.0 0.0 20.0 4 weeks No 13 acid Example Ellagic 0.04 2.0 0.0 20.0 4weeks No 14 acid Example Ellagic 0.04 2.0 0.0 20.0 4 weeks No 15 acidExample Ellagic 0.04 2.0 0.0 20.0 4 weeks No 16 acid Example Ellagic0.04 2.0 0.0 20.0 4 weeks No 17 acid Example Ellagic 0.04 2.0 0.0 20.0 4weeks No 18 acid Example Ellagic 0.04 2.0 0.0 20.0 4 weeks No 19 acidExample Ellagic 0.04 2.0 0.0 20.0 4 weeks No 20 acid Example Ellagic0.03 2.0 0.0 20.0 4 weeks No 21 acid Example Ellagic 0.04 2.0 0.0 20.0 4weeks No 22 acid Example Ellagic 0.04 2.0 0.0 20.0 4 weeks No 23 acidExample Ellagic 0.04 2.0 0.0 20.0 4 weeks No 24 acid Example Ellagic0.04 2.0 0.0 20.0 4 weeks No 25 acid Example Ellagic 0.03 2.0 0.0 20.0 4weeks No 26 acid Example Ellagic 0.04 2.0 0.0 20.0 4 weeks No 27 acidExample Ellagic 0.04 2.0 0.0 20.0 4 weeks No 28 acid Example Ellagic0.04 2.0 0.0 20.0 4 weeks No 29 acid Example Ellagic 0.03 2.0 0.0 20.0 4weeks No 30 acid Example Ellagic 0.03 2.0 0.0 20.0 4 weeks No 31 acidExample Ellagic 0.04 2.0 0.0 20.0 4 weeks No 32 acid Example Ellagic0.04 2.0 0.0 20.0 4 weeks No 33 acid Example Ellagic 0.04 2.0 0.0 20.0 4weeks No 34 acid Example Ellagic 0.04 2.0 0.0 20.0 4 weeks No 35 acidExample Ellagic 0.04 2.0 0.0 20.0 4 weeks No 36 acid Example Ellagic0.04 2.0 0.0 20.0 4 weeks No 37 acid Example Ellagic 0.04 2.0 0.0 20.0 4weeks No 38 acid Example Ellagic 0.04 2.0 0.0 20.0 4 weeks No 39 acidExample Ellagic 0.03 2.0 0.0 20.0 4 weeks No 40 acid Example Ellagic0.03 2.0 0.0 20.0 4 weeks No 41 acid Example Ellagic 0.04 2.0 0.0 20.0 4weeks No 42 acid Example Ellagic 0.03 2.0 0.0 20.0 4 weeks No 43 acid¹⁾precipitate amount of a poorly soluble/insoluble material undissolvedduring the preparation of an oligomer composite containing a poorlysoluble/insoluble material ²⁾after the storage period of 4 weeks at 4°C., observation of the presence of precipitate

TABLE 8 Input amount of oligomer composite Precipitate containing aamount poorly during soluble/insoluble Precipitate Poorly preparationmaterial amount soluble/ of oligomer during during Presence insolublecomposite redissolution redissolution Solubility Storage of Examplematerial (g)¹⁾ (g) (g) (mg/ml) period precipitate²⁾ Example Ellagic 0.042.0 0.0 20.0 4 weeks No 44 acid Example Ellagic 0.04 2.0 0.0 20.0 4weeks No 45 acid Example Ellagic 0.04 2.0 0.0 20.0 4 weeks No 46 acidExample Ellagic 0.04 2.0 0.0 20.0 4 weeks No 47 acid Example Ellagic0.04 2.0 0.0 20.0 4 weeks No 48 acid Example Ellagic 0.04 2.0 0.0 20.0 4weeks No 49 acid Example Ellagic 0.03 2.0 0.0 20.0 4 weeks No 50 acidExample Ellagic 0.03 2.0 0.0 20.0 4 weeks No 51 acid Example Ellagic0.04 2.0 0.0 20.0 4 weeks No 52 acid Example Ellagic 0.04 2.0 0.0 20.0 4weeks No 53 acid Example Ellagic 0.04 2.0 0.0 20.0 4 weeks No 54 acidExample Ellagic 0.04 2.0 0.0 20.0 4 weeks No 55 acid Example Ellagic0.03 2.0 0.0 20.0 4 weeks No 56 acid Example Ellagic 0.04 2.0 0.0 20.0 4weeks No 57 acid Example Ellagic 0.04 2.0 0.0 20.0 4 weeks No 58 acidExample Ellagic 0.04 2.0 0.0 20.0 4 weeks No 59 acid Example Ellagic0.04 2.0 0.0 20.0 4 weeks No 60 acid Example Ellagic 0.03 2.0 0.0 20.0 4weeks No 61 acid Example Ellagic 0.04 2.0 0.0 20.0 4 weeks No 62 acidExample Ellagic 0.04 2.0 0.0 20.0 4 weeks No 63 acid Example Ellagic0.04 2.0 0.0 20.0 4 weeks No 64 acid Example Ellagic 0.04 2.0 0.0 20.0 4weeks No 65 acid Example Ellagic 0.03 2.0 0.0 20.0 4 weeks No 66 acidExample Ellagic 0.04 2.0 0.0 20.0 4 weeks No 67 acid Example Ellagic0.04 2.0 0.0 20.0 4 weeks No 68 acid Example Ellagic 0.04 2.0 0.0 20.0 4weeks No 69 acid Example Ellagic 0.03 2.0 0.0 20.0 4 weeks No 70 acidExample Ellagic 0.03 2.0 0.0 20.0 4 weeks No 71 acid Example Ellagic0.04 2.0 0.0 20.0 4 weeks No 72 acid Example Ellagic 0.04 2.0 0.0 20.0 4weeks No 73 acid Example Ellagic 0.04 2.0 0.0 20.0 4 weeks No 74 acidExample Ellagic 0.04 2.0 0.0 20.0 4 weeks No 75 acid Example Ellagic0.04 2.0 0.0 20.0 4 weeks No 76 acid Example Ellagic 0.04 2.0 0.0 20.0 4weeks No 77 acid Example Ellagic 0.04 2.0 0.0 20.0 4 weeks No 78 acidExample Ellagic 0.04 2.0 0.0 20.0 4 weeks No 79 acid Example Ellagic0.03 2.0 0.0 20.0 4 weeks No 80 acid Example Ellagic 0.03 2.0 0.0 20.0 4weeks No 81 acid Example Ellagic 0.04 2.0 0.0 20.0 4 weeks No 82 acidExample Ellagic 0.04 2.0 0.0 20.0 4 weeks No 83 acid Example Ellagic0.04 2.0 0.0 20.0 4 weeks No 84 acid Example Ellagic 0.04 2.0 0.0 20.0 4weeks No 85 acid Example Ellagic 0.04 2.0 0.0 20.0 4 weeks No 86 acidExample Ellagic 0.04 2.0 0.0 20.0 4 weeks No 87 acid Example Ellagic0.04 2.0 0.0 20.0 4 weeks No 88 acid Example Ellagic 0.04 2.0 0.0 20.0 4weeks No 89 acid Example Ellagic 0.04 2.0 0.0 20.0 4 weeks No 90 acidExample Ellagic 0.03 2.0 0.0 20.0 4 weeks No 91 acid Example Ellagic0.04 2.0 0.0 20.0 4 weeks No 92 acid Example Ellagic 0.04 2.0 0.0 20.0 4weeks No 93 acid Example Ellagic 0.04 2.0 0.0 20.0 4 weeks No 94 acidExample Ellagic 0.03 2.0 0.0 20.0 4 weeks No 95 acid ¹⁾precipitateamount of a poorly soluble/insoluble material undissolved during thepreparation of an oligomer composite containing a poorlysoluble/insoluble material ²⁾after the storage period of 4 weeks at 4°C., observation of the presence of precipitate

TABLE 9 Input amount of oligomer composite Precipitate containing aamount poorly during soluble/insoluble Precipitate Poorly preparationmaterial amount soluble/ of oligomer during during Presence insolublecomposite redissolution redissolution Solubility Storage of Examplematerial (g)¹⁾ (g) (g) (mg/ml) period precipitate²⁾ Example Ellagic 0.042.0 0.0 20.0 4 weeks No 96 acid Example Ellagic 0.04 2.0 0.0 20.0 4weeks No 97 acid Example Ellagic 0.04 2.0 0.0 20.0 4 weeks No 98 acidExample Ellagic 0.04 2.0 0.0 20.0 4 weeks No 99 acid Example Ellagic0.04 2.0 0.0 20.0 4 weeks No 100 acid Example Ellagic 0.03 2.0 0.0 20.04 weeks No 101 acid Example Ellagic 0.04 2.0 0.0 20.0 4 weeks No 102acid Example Ellagic 0.04 2.0 0.0 20.0 4 weeks No 103 acid ExampleEllagic 0.03 2.0 0.0 20.0 4 weeks No 104 acid Example Ellagic 0.04 2.00.0 20.0 4 weeks No 105 acid Example Ellagic 0.04 2.0 0.0 20.0 4 weeksNo 106 acid Example Ellagic 0.04 2.0 0.0 20.0 4 weeks No 107 acidExample Ellagic 0.04 2.0 0.0 20.0 4 weeks No 108 acid Example Ellagic0.04 2.0 0.0 20.0 4 weeks No 109 acid Example Ellagic 0.03 2.0 0.0 20.04 weeks No 110 acid Example Ellagic 0.03 2.0 0.0 20.0 4 weeks No 111acid Example Ellagic 0.04 2.0 0.0 20.0 4 weeks No 112 acid ExampleEllagic 0.04 2.0 0.0 20.0 4 weeks No 113 acid Example Ellagic 0.04 2.00.0 20.0 4 weeks No 114 acid Example Ellagic 0.03 2.0 0.0 20.0 4 weeksNo 115 acid Example Ellagic 0.04 2.0 0.0 20.0 4 weeks No 116 acidExample Ellagic 0.04 2.0 0.0 20.0 4 weeks No 117 acid Example Ellagic0.03 2.0 0.0 20.0 4 weeks No 118 acid Example Ellagic 0.04 2.0 0.0 20.04 weeks No 119 acid Example Ellagic 0.04 2.0 0.0 20.0 4 weeks No 120acid Example Amentoflavone 0.03 2.0 0.0 20.0 4 weeks No 121 ExampleDiosmetin 0.05 2.0 0.0 20.0 4 weeks No 122 Example Berginin 0.05 5.0 0.050.0 4 weeks No 123 Example Univestin 0.06 4.0 0.0 40.0 4 weeks No 124Example Apigenin 0.03 2.0 0.0 20.0 4 weeks No 125 Example Resveratrol0.03 2.0 0.0 20.0 4 weeks No 126 Example Isoflavones 0.06 4.0 0.0 40.0 4weeks No 127 Example Salicylic 0.01 5.0 0.0 50.0 4 weeks No 128 acidExample Alpha 0.02 4.0 0.0 40.0 4 weeks No 129 lipoic acid ExampleCaffeine 0.00 5.0 0.0 50.0 4 weeks No 130 Example Tocopherol 0.01 4.00.0 40.0 4 weeks No 131 Example Docosahexaenoic 0.01 4.0 0.0 40.0 4weeks No 132 acid Example Eicosapentaenoic 0.01 4.0 0.0 40.0 4 weeks No133 acid Example Conjugated 0.01 4.0 0.0 40.0 4 weeks No 134 linolenicacid Example Ginkgobiloba 0.02 2.0 0.0 20.0 4 weeks No 135 leaf extractExample Red 0.03 2.0 0.0 20.0 4 weeks No 136 ginseng extract ExampleSoybean 0.03 4.0 0.0 40.0 4 weeks No 137 extract Example Epigalloca 0.015.0 0.0 50.0 4 weeks No 138 techin gallate ¹⁾precipitate amount of apoorly soluble/insoluble material undissolved during the preparation ofan oligomer composite containing a poorly soluble/insoluble material²⁾after the storage period of 4 weeks at 4° C., observation of thepresence of precipitate

As shown in Tables 7 to 9, with respect to the examples using two typesof the natural polymer oligomers, it may be understood that when thepoorly soluble/insoluble materials were added to the oligomer compositesolutions to be encapsulated and then precipitates were almost notgenerated during centrifugation of the reaction solutions, and most ofthe poorly soluble/insoluble materials were encapsulated in the oligomercomposites.

Precipitates were not generated even in the case that the preparednatural polymer oligomer composite powders containing the poorlysoluble/insoluble material were redissolved and centrifuged, andprecipitation was not observed after storing of centrifuged supernatantsat 4° C. for 4 weeks.

Thus, when the poorly soluble/insoluble materials were encapsulatedthrough the formation of oligomer composites by using oligomers derivedfrom two types of hydrophilic natural polymers, solubilities of thepoorly soluble/insoluble materials may be improved and dissolutionstability may be increased. Therefore, the poorly soluble/insolublematerials may not only be used as a functional raw material of cosmeticsindustry, but application thereof may also be extended to otherindustries (food and medicine, etc.) requiring solubilization of thepoorly soluble/insoluble materials.

According to a method of solubilizing a poorly soluble/insolublematerial through formation of an oligomer composite of the presentinvention, an oligomer structure having a hydrophobic cavity structureis formed by physical bonding between molecules and a poorlysoluble/insoluble material is encapsulated in the oligomer structure.Thus, dissolution stability of the poorly soluble/insoluble material inan aqueous solution may be increased.

Also, since precipitation due to redissolution of the poorlysoluble/insoluble materials is prevented, the oligomer compositeencapsulating the poorly soluble/insoluble material has excellentdissolution stability, and inherent biological activity of the poorlysoluble/insoluble material may also be maintained as it is, because achemical reaction is not accompanied.

The foregoing oligomer composite encapsulating the poorlysoluble/insoluble material may improve water solubility and dissolutionstability of an active substance.

Since the oligomer composite encapsulating the poorly soluble/insolublematerial thus prepared has excellent dissolution stability, the oligomercomposite may not only be used as a functional raw material of cosmeticsindustry, but application thereof may also be extended to otherindustries (food and medicine, etc.) requiring solubilization of thepoorly soluble/insoluble materials.

A method of solubilizing a poorly soluble/insoluble active materialthrough formation of an oligomer composite according to embodiments willbe described in detail with reference to the accompanying drawings. Theinvention may, however, be embodied in many different forms and shouldnot be construed as being limited to the embodiments set forth herein;rather, that alternate embodiments included in other retrogressiveinventions or falling within the spirit and scope of the presentdisclosure can easily be derived through adding, altering, and changing,and will fully convey the concept of the invention to those skilled inthe art.

What is claimed is:
 1. A method of solubilizing a poorlysoluble/insoluble active material through formation of an oligomercomposite, the method comprising: a first operation of preparing anoligomer composite having a hydrophobic cavity structure formed thereinby mixing and dissolving oligomers derived from two types of hydrophilicnatural polymers in water; a second operation of adding a poorlysoluble/insoluble material to the oligomer composite prepared in thefirst operation to encapsulate the poorly soluble/insoluble material inthe hydrophobic cavity structure, of the oligomer composite, which isobtained in the first operation, a third operation of removing aresidual poorly soluble/insoluble material unencapsulated in theoligomer composite by filtration or centrifugation of a reactionsolution; and a fourth operation of removing water and an organicsolvent (when used) from the reaction solution having the residualmaterial removed therefrom to dry, wherein the oligomers derived fromthe natural polymers are two selected from the group consisting ofxanthan gum, acacia gum, guar gum, arabic gum, agar, alginic acid,pectin, carboxyalkylcellulose, maltodextrin, and dextrin, wherein thepoorly soluble/insoluble material is any one selected from the groupconsisting of: polyphenols, wherein the polyphenols are selected fromthe group consisting of amentoflavone, ellagic acid, apigenin, berginin,diosmetin, univestin, resveratrol, isoflavones, and catechin; oily fattyacids, wherein the fatty acids are selected from the group consisting ofsalicylic acid, alpha lipoic acid, caffeine, tocopherol, DHA(docosahexaenoic acid), EPA (eicosapentaenoic acid), and CLA (conjugatedlinolenic acid); and natural extracts containing a ginkgo biloba leafextract, and a red ginseng extract.
 2. The method of claim 1, wherein aweight ratio of the natural polymer oligomers with respect to a totalweight of a total solid content is in a range of about 1:1 to about1:10, and the natural polymer oligomers are mixed within a temperaturerange of about 20° C. to about 80° C.
 3. The method of claim 1, whereinthe poorly soluble/insoluble material is added in an amount range ofabout 0.1 wt % to about 99 wt % based on a total solid content and ismixed within a temperature range of about 20° C. to about 80° C.
 4. Themethod of claim 1, wherein the poorly soluble/insoluble material in thesecond operation is added by being dissolved in an organic solvent. 5.The method of claim 4, wherein the organic solvent is any one selectedfrom the group consisting of methanol, ethanol, acetone, THF(tetrahydrofuran), and AN (acetonitrile).